The study of class I genes/proteins up until recently has focused on class Ia (classical) molecules and their role in presentation of peptide antigens to CD8 T cells. However, there is now great interest in the study of nonclassical class I molecules which play many important and unique roles in the immune response to infectious agents. In this grant we will characterize and dissect the function of several nonclassical class I molecules. Based on the expertise of our group, we will focus on the following class I molecules/genes; viz. Qa-1, mFcRn. Several approaches will be used to delineate their function which include the analysis of the immune response in mice selectively lacking class Ia molecules, the expression of class I molecules (classical and nonclassical) in hepatocytes of normal and immunostimulated animals, the role of the mFcRn is controlling the level of ligands which bind this receptor, and a characterization of newly discovered genes in the M region. This project will lead to an understanding of 1) the role that nonclassical class I molecules play in the response to bacterial and viral infection, 2) the expression of class I molecules in the liver in normal and diseased states together with the factors that control their expression, 3) a molecular, structural and functional characterization of M region molecules, 4) and how the mFcRn can be used to increase the therapeutic efficiency of cytokines.